The overall goal of this proposal is to increase our understanding of the hypoxic response in the adult mouse. Members of the PAS domain family of transcription factors have important roles in development and in response to environmental stresses including hypoxic-responsiveness. The first identified hypoxic-responsive member of this family, hypoxia inducible factor I (HIFI), activates a number of target genes including the erythropoeitin promoter. Endothelial PAS domain protein 1 (EPAS1), the second hypoxic-responsive member of the PAS family, is expressed at high levels in vascular endothelial cells, carotid body glomus cells, and pulmonary pneumocytes. Despite the observation that HIF1 and EPAS1 can bind to similar DNA regulatory sequences in model promoters, it is likely that HIF1 and EPAS1 play distinctive regulatory roles as evident by the differences in sites of expression as well as stage and description of embryonic lethality for the respective knockouts. We hypothesize that hypoxic regulators such as EPAS1 are fundamentally involved in the pathogenesis underlying hypertension, sleep apnea, and heart failure. The specific aims of this project are to: (1) construct a preconditional strain for use in generating conditional knockouts for EPAS1; (2) construct transgenic mice that express cre in a tissue-restricted manner in anatomic sites that overlap EPAS1 expression; (3) generate knockout mice lacking EPAS1 in endothelial or glomus cells and characterize the cardiovascular function of the resultant EPAS1- deficient mice under normoxic as well as intermittent hypoxic conditions. The principal investigator has completed a residency in internal medicine, a fellowship in cardiology, and most recently a postdoctoral fellowship in the department of biochemistry. His doctoral research involved molecular biological studies of HIV gene regulation. His postdoctoral research involved defining the neurobiological role of a neural-restricted transcription factor in a mouse knockout model. He has just recently been appointed an assistant professor in the cardiology division. The proposed research on physiologic aspects of cardiovascular function will result in the acquisition of research skills in experimental areas novel to this investigator. His sponsors and advisory committee members will serve as important resources due to their expertise in cardiovascular biology and in other areas directly relevant to the pursuit of these experimental aims. The CIDA grant would aid in development of the principal investigator into an independent research leader in cardiovascular biology whose career goals are to study signal transduction in the adult mammalian cardiovascular system.